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Hydantoin-substituted 4,6-dichloroindole-2-carboxylic acids as ligands with high affinity for the glycine binding site of the NMDA receptor.

Abstract：

:A novel series of C-3 substituted 4,6-dichloroindole-2-carboxylic acids was synthesized to investigate the influence of different hydrogen-bond donor and acceptor groups at this specific position on the affinity to the glycine site of the NMDA receptor. These novel 3-indolylmethyl derivatives with ring-open (amines, sulfonamides, amides, ureas) and cyclic substituents (imidazolidin-2-ones, (thio)hydantoins) led to the discovery that compounds bearing a hydantoin substituent at the C-3 position of the indole nucleus are the most promising ones. In this series the hydantoins, ureas, and imidazolidin-2-ones were identified as very potent inhibitors of the binding of the glycine site specific ligand [(3)H]MDL 105,519 to pig cortical brain membranes. Since the hydantoins can be produced via a versatile synthetic approach, further amendments of the hydantoin-substituted compounds were conducted to elucidate the influence of aromatic and aliphatic moieties at position 3 of the hydantoin as well as of sterically hindered compounds (5-substituted hydantoins). On the basis of the pharmacological data obtained in displacement experiments with [(3)H]MDL 105,519 and the emerging structure-activity relationships, we confirm the existing pharmacophore model that suggests a hydrogen-bond acceptor and an aromatic substituent at position 3 of the indole as the key features for high affinity. Log P values indicate brain permeability and selected compounds showed anticonvulsant activity in vivo. Binding studies for the sodium channel (site 2) were also performed on some selected compounds.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Jansen M,Potschka H,Brandt C,Löscher W,Dannhardt G

doi

10.1021/jm020955n

keywords:

subject

Has Abstract

pub_date

2003-01-02 00:00:00

pages

64-73

issue

1

eissn

0022-2623

issn

1520-4804

journal_volume

46

pub_type

杂志文章

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